NOVEL ARYLOXYALKYLTHIOIMIDAZOLES AS INHIBITORS OF ACYL-COA - CHOLESTERAL-O-ACYLTRANSFERASE

A series of aryloxyalkylthioimidazoles have been synthesized and evalu ated for their ability,to interfere with the enzyme acyl-CoA (choleste rol-O-acyltransferase) (ACAT, EC 2.3.1.26). Most of the molecules poss essed a good in vitro ACAT inhibitory activity with IC50 values rangin g between 0.1 and 2.0 mu M Some of them, eg, 2-{5-[(4-isobutoxycarbony l)phenoxy]-pentylthio} -4,5-diphenylimidazole 13, henoxy]-2-oximinopro pylthio}-4,5-diphenylimidazole 21, arbonyl)phenoxy]-2-hydrazonecarboxa midepropylthio) -4,5-diphenylimidazole 26, -[5-(2-pyridoxy)-pentylthio ]-4,5-diphenylimidazole 40 and droxy)phenylthio]pentylthio}-4,5-diphen ylimidazole 42, were more potent (range of activity 10-90 nM). They we re also more potent with respect to the reference CI-976. When adminis tered orally in hyperlipemic rats, at 10 and 50 mg/kg doses, some repr esentative compounds, like henoxy]-2-hydroxypropylthio}-4,5-diphenylim idazole 1, 13 and 26, reduced VLDL/LDL-associated cholesterol levels b y 30-50% and increased HDL cholesterol levels by 15-50%. In addition, liver accumulation of esterified cholesterol was counteracted (50-80% reduction) and liver ACAT ex vivo activity was decreased by 70-85%. Fi nally, the good efficacy displayed in an endogenous model of hypertrig lyceridemia strongly supports the hypothesis of a good systemic availa bility, which constitutes one of the principal properties of a valuabl e ACAT inhibitor.